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GAS6/TAM Axis as Therapeutic Target in Liver Diseases
Anna Tutusaus1,2, Albert Morales1,2, Pablo García de Frutos1,3
1Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalunya, Spain.
Abstract:
TAM (TYRO3, AXL, and MERTK) protein tyrosine kinase membrane receptors and their vitamin K-dependent ligands GAS6 and protein S (PROS) are well-known players in tumor biology and autoimmune diseases. In contrast, TAM regulation of fibrogenesis and the inflammation mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and, ultimately, liver cancer has recently been revealed. GAS6 and PROS binding to phosphatidylserine exposed in outer membranes of apoptotic cells links TAMs, particularly MERTK, with hepatocellular damage. In addition, AXL and MERTK regulate the development of liver fibrosis and inflammation in chronic liver diseases. Acute hepatic injury is also mediated by the TAM system, as recent data regarding acetaminophen toxicity and acute-on-chronic liver failure have uncovered. Soluble TAM-related proteins, mainly released from activated macrophages and hepatic stellate cells after hepatic deterioration, are proposed as early serum markers for disease progression. In conclusion, the TAM system is becoming an interesting pharmacological target in liver pathology and a focus of future biomedical research in this field.
Insights
The TAM system, involving TYRO3, AXL, and MERTK receptors, plays a key role in liver diseases like MASH and cancer. Its proteins are emerging as potential biomarkers for disease progression and therapeutic targets.
Area of Science:
- Cell biology
- Immunology
- Hepatology
Background:
- The TAM (TYRO3, AXL, MERTK) receptor tyrosine kinases and their ligands (GAS6, PROS) are implicated in tumor biology and autoimmune disorders.
- Recent research highlights the TAM system's role in liver fibrogenesis, inflammation, and metabolic dysfunction-associated steatohepatitis (MASH).
Purpose of the Study:
- To elucidate the role of the TAM system in liver pathology, including MASH, cirrhosis, and liver cancer.
- To investigate TAM-mediated mechanisms in hepatocellular damage and acute hepatic injury.
- To explore soluble TAM-related proteins as potential biomarkers for liver disease progression.
Main Methods:
- Review of existing literature on TAM receptors, ligands, and their involvement in liver diseases.
- Analysis of data concerning acetaminophen toxicity and acute-on-chronic liver failure.
- Investigation of TAM receptor roles in liver fibrosis and inflammation.
Main Results:
- GAS6/PROS binding to apoptotic cells links TAMs, especially MERTK, to hepatocellular damage.
- AXL and MERTK are crucial in developing liver fibrosis and inflammation in chronic liver conditions.
- The TAM system mediates acute hepatic injury, as seen in acetaminophen toxicity and acute-on-chronic liver failure.
Conclusions:
- The TAM system is increasingly recognized as a significant factor in liver pathology.
- Soluble TAM-related proteins released during hepatic deterioration may serve as early serum markers.
- The TAM system presents a promising pharmacological target for liver disease treatment and future research.
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